PTPN2 mutations cause epithelium-intrinsic barrier loss that synergizes with mucosal immune hyperactivation.

It is clear that excessive mucosal immune activation and intestinal barrier dysfunction both contribute to inflammatory bowel disease (IBD) pathogenesis. T cell protein tyrosine phosphatase (TCPTP), which extinguishes signaling in immune cells, is linked to IBD and other immune-mediated diseases. In this issue of the JCI, Marchelletta and Krishnan et al. demonstrate that, in intestinal epithelial cells, TCPTP regulates tight junction permeability in vivo. Intestinal epithelial TCPTP loss potentiated cytokine-induced barrier loss, and this synergized with effects of TCPTP loss in immune cells. This work implicates a single mutation as the cause of distinct functional aberrations in diverse cell types and demonstrates how one genetic defect can drive multihit disease pathogenesis.